| Summary: | 碩士 === 國立陽明大學 === 遺傳學研究所 === 90 === Prader-Willi syndrome (PWS) is a complex neurobehavioral disorder. It is known human chromosome 15q11-13 is the critical region for PWS. Loss of the paternally expressed genes within this region caused PWS phenotypes. Targeted mutagenesis of many mouse homologues of the human candidate PWS genes does not appear to result in any of the features of PWS. Only Ndn-knockout mice represent some of the classical phenotypes of PWS. However, the phenotypes vary from no obvious abnormality to postnatal lethality. Magel2 is a neighbor gene with Ndn. They both belong to MAGE family and have 70% amino acid similarity at c-terminal region. And they both abundant in fetal and adult brain. Based on those similarity, we question that the genetic background is the only cause resulted in the differential penetrance of Ndn null mice.
To compare their functions, the expression profiles of Magel2 and Ndn were analyzed. Although their expression is similar at mouse embryonic stage. However, their distribution in brain and cell types of in P19 in vitro differentiation system are not the same. Moreover, data from microarray also suggest their distinct roles in PWS.
To investigate functions of Magel2 and Ndn in vivo, single gene targeted and double gene targeted ES cell clones were generated. These mouse models will become potential tools to study etiology of PWS.
Because of the imprinting nature, we also examined the DNA methylation patterns of Magel2 and Ndn gene. We used methylation-specific Southern analysis to clarify the methylation status at specific restriction site. Our data reconfirmed the previous studies of Snrpn locus. In the 5’ regions of Ndn and Magel2 gene, the active, paternal allele were hypomethylated, but the silent, maternal allele was hypermethylated. And we identified a brain-specific hypomethylated site at Magel2 5’ UTR region just before the start codon. However, the biological meanings of this site require further studies.
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